The invention relates to novel pharmaceutical compositions of lipase-containing products for oral administration, in particular pancreatin and pancreatin-containing products, or of enzyme products containing at least one lipase of non-animal, especially microbial origin, in which the pharmaceutical compositions provide improved lipolytic activity, in particular a stabilization of the lipase in the acidic pH range. These novel pharmaceutical compositions contain a system which comprises at least one surfactant and one co-surfactant, and are self-emulsifiable on contact with a hydrophilic and a lipophilic phase. The pharmaceutical compositions of the invention are well suited for the treatment and/or inhibition of maldigestion, in particular maldigestion based on chronic exocrine pancreatic insufficiency, in mammals and humans.
Maldigestion in mammals and humans is usually based on a deficiency of digestive enzymes, in particular on a deficiency of endogenous lipase, but also of protease and/or amylase. The cause of such a deficiency of digestive enzymes is frequently a hypofunction of the pancreas (=pancreatic insufficiency), the organ which produces the most, and the most important, endogenous digestive enzymes. If the pancreatic insufficiency is pathological, this may be congenital or acquired. Acquired chronic pancreatic insufficiency may, for example, be ascribed to alcoholism. Congenital pancreatic insufficiency may, for example, be ascribed to the congenital disease cystic fibrosis. Consequences of the deficiency of digestive enzymes may include severe symptoms of under-nutrition and malnutrition, which may be accompanied by increased susceptibility to secondary illnesses.
Substitution with similarly-acting exogenous digestive enzymes or mixtures of digestive enzymes has proved effective treatment for a deficiency in endogenous digestive enzymes. At present, pharmaceutical preparations (=preparations) which contain porcine pancreatin (=pancreatin) are frequently used for this purpose. Such mixtures of digestive enzymes obtained from the pig pancreas comprise lipases, amylases and proteases, and can be used effectively for enzyme substitution therapy in humans due to the great similarity of the enzymes and accompanying substances contained therein to the contents of human pancreatic juices. For example, processes are described in U.S. Pat. No. 4,019,958 (=DE 25 12 746) and German Patent Publication No. DE 42 03 315 by which pancreatin is obtained as a natural enzyme mixture by extraction from porcine pancreas and subsequently is converted in a known manner into the desired pharmaceutical form. The pancreatic enzymes are usually administered orally in the form of solid preparations. Pancreatin is thus commercially available, for example under the trade name Kreon®, in the form of granules, pellets or capsules with enteric-coated micropellets.
In order that, when taken orally, the administered enzyme mixtures are not irreversibly denatured in the stomach by gastric acid and proteolytic enzymes, such as pepsin present there, it is necessary to provide the enzyme mixtures with an enteric coating. Such a coating enables the enzyme mixtures to pass intact through the stomach to their point of action, the duodenum, where, due to the neutral to slightly alkaline conditions prevailing there, the protective layer is broken down and the enzymes are released. Like the endogenous pancreatic enzymes of healthy humans, the orally supplied enzymes can exert their enzymatic action, in particular amylolytic, lipolytic and proteolytic activity, there. Such solid pancreatin formulations which can be coated with an enteric film are described e.g. in U.S. Pat. No. 4,280,971 (=EP 21, 129).
U.S. Pat. No. 5,378,462 (=EP 583,726) describes pancreatin micropellet cores coatable with an enteric film having a pancreatin content of 65-85%, in particular 75-80%, by weight which have a bulk density of 0.6 g/ml to 0.85 g/ml, consisting essentially of pancreatin, polyethylene glycol 4000 and low-viscosity paraffin, containing per 100 parts by weight pancreatin: 15-50, in particular 20-30, parts by weight polyethylene glycol 4000; and 1.5-5, in particular 2-3, parts by weight low-viscosity paraffin, and having a spherical to ellipsoid form, the sphere diameter or the minor axis being in the range of 0.7-1.4 mm, in particular 0.8-1.2 mm, and having a particle-size distribution in which at least 80% of the pancreatin micropellet cores have a ratio of minor axis to major axis in the range of 1:1 to 1:2.
Furthermore, U.S. Pat. No. 5,993,806 (=EP 826,375) describes the use of lecithin as a stabilizing agent added to water-soluble pharmaceutical preparations of mixtures of digestive enzymes which contain protease/lipase mixtures, in particular pancreatin, and which are suitable for the preparation of aqueous solutions for continuous introduction into the gastrointestinal tract via probes. The lecithin is added to stabilize the mixtures of digestive enzymes against a decrease in the lipolytic activity under the influence of moisture.
In the case of pharmaceutical formulations not coated with enteric films, it is known that at the point of action of the enzymes, in the duodenum, often only a very small proportion of the lipase contained in the pharmaceutical preparation and taken therewith is active. Thus in German Patent Publication No. DE 36 42 853 such enzyme deactivation is ascribed to insufficient neutralization of the gastric acid in the duodenum. Whereas in a healthy human the postprandial intraduodenal pH value is about 6, patients with pancreatic insufficiency only have a pH value of about 4. At this pH value, the lipase contained in the pharmaceutical preparation has only one fifth of the activity that it would otherwise have at a pH value of 6.